Preparation of stable concentrated solutions of therapeutically useful calcium compounds



I Patented Au s, 1939 PREPARATION SOLUTIONS FUL CALCIUM COMPOUNDS Richard Brown, Jamaica, N.

8: Company, Brooklyn,

tion of New Jersey No Drawing. Original Serial No. 220,330.

1:, Brooklyn, and

F STABLE CONCENTRATED 0F EUTIOALLY USE- Ellis V. Charles N. Y., a corpora- Y., asslsnors to application June 20, 1938. Divided and this applicaon March 14, 1939, No. 261,770

This invention relates to the preparation of therapeutically useful stable calcium solutions of high concentration, and is a division of our copending application Serial 5 20, 1938.

Calcium gluconate has been generally accepted by the medical profession as an eil'ective and harmless compound for the administration of calcium either orally or intravenously. However, calcium gluconate is of relatively low solubility in water (approximately 3% at room temperaand are not practicable for injection stabilize such solutions by various methods but so so far as we have been able to discover most of these are of limited eilectiveness and none are entirely reliable at very high concentrations.

We have now found that the product resulting from catalytic hydrogenation of calcium 5-ketod-gluccnate consists of a highly soluble mixture of therapeutically useful calcium salts, and moreover can be used to stabilizeconcentrated calcium gluconate solutions.

Neither 5-keto-gluconic acid nor its known so derivatives are of great stability,.so that it was impossible to predict the conditions under which it could be hydrogenated without,serious decomposition. Moreover, the calcium salt is so nearly insoluble in water that it could not have been expected to react.

It was found experimentally that Ipatiefls conditions for the reduction of sugars, heating the reactionmixture at 130 C. under a pressure of about 100 atmospheres in the presence of a nickel catalyst, completely destroyed the calcium 5-keto-gluconate. It is mown in the art that metals or the platinum group usually catalyze hydrogenation under conditions less severe than those required for nickel. The calcium 5-ketoi gluconate was therefore subjected to treatment with hydrogen at room temperature under 100 atmospheres pressure and in the presence of a palladium catalyst, but no visible hydrogen absorption took place. The temperature was then raised to 100 C. in the course of several hours, but still without result. 7

We have found, however, that the nearly insoluble calcium 5-keto-gluconate may be successfully hydrogenated in aqueous suspension in the presence of a Rainey nickel catalyst at a tem- No. 220,330, filed June Many attempts have been made to perature of 25 to C. with a hydrogen pressure some atm or more, as disclosed in our above-mentioned application Serial No. 220,- 330. Inasmuch as the calcium S-keto-gluconate and its reduction products are neutral substances. -6 the nickel catalyst is unailected and can be used repeatedly. For the same reason corrosion-resisting equipment is not necessary and reaction can be carried out in an ordinary iron autoclave. At pressures below 80 atmospheres, hydrogena- 10 tion is rather slow at the comparatlveLv low temperature used, but for the preparation of a pure product temperatures above 65 C. are not advisable because they cause decomposition. Considerably higher pressures may be used without 15 harmful eiiect. At. any pressure substantially above 80 atmospheres with an emcient nickel catalyst hydrogenation takes place at a practical rate at temperatures as low as 40 0., and even proceeds slowly at room temperature.

The hydrogenation product is a mixture of calcium-l-idonate and calcium d-gluconate. Whenthe reaction temperature has been kept below 65 C., the solution of calcium salts resulting from the hydrogenation, aiter removal of the catalyst by filtration, is sufliciently pure for pharmaceutical use. Many eflorts have been made to produce a therapeutically useful calcium salt mixture of high solubility, but with little success. It was therefore not to be that a natural mixture of calcium idonate and calcium gluconate resulting from the hydrogenation of calcium-S-keto-gluconate would serve the purpose. However, it was found that this product, an amorphous solid when dry, is so soluble in water that the concentration of its aqueous solutions is limited only by practical considerations such as viscosity.

Example-240 grams of calcium d-keto-gluconate containing three molecules of ter of crystallization (CaH9O-1):Ca.3 are suspended in 1000 cc. of distilled water and treated with 35 g. of Rainey nickel catalyst. The snsion is placed in an autoclave and heated at 60 C. with agitation under a hydrogen pressure of atmospheres. After some 4 hours heating. the absorption of hydrogen ceases. The peiis then released and the solution filtered from the catalyst, which can be reused without further treatment. Boiling asample of the filtrate with Fehling's solution shows the absence of reducing substances, indicating complete hydrogenation.

The colorless filtrate is evaporated to yness either under vacuum or on a bath; or al- 5 In either case, the product is an amorphous mix ure of calcium l-idonate and calcium d-gluconate. This mixture is not crystallizable. It

,is useiul in calcium therapy, being non toxic and moresoluble than any previously known calcium preparation. It is also possible to isolate from the mixture substantial amounts of l-idonic acid in 1899). Dibenxal l-idonic acid of melting point 225' C. can be ob ed from the hydrogenated mixture. Hydrolysis oi the dibenzal compound by means 01 dilute sulfuric acid gives a solution 01' pure l-idonic acid.

The hydrogenation product forms a stable solution with any proportion oi water, or it may be used to stabilize solutions already containing calcium gluconate. For example, it 100 grams of the dried hydrogenation mixture containing calcium idonate are added to an aqueous solution oi 50 grams of calcium-d-gluconate in 600 cc. of water, the solution will remain stable. Such a solution obviously contains 20% 0! calcium aldonates, and since calcium idonate is an isomer of calcium gluconate the available calcium content is equivalent to that of a 20% solution of calcium gluconate.

The invention claimed is:

prises adding to the for instance by the method used by van lkenstein andde Bruyn (Rec. trav. 182305,

More highly concentrated solutions oi calcium gluconate may be stabilized by the addition of a larger proportion oi calcium idonate, whether added as such or as a constituent of our hydrogenation product.

1. Process of stabilizing an over-saturated aqueous solution of calcium gluconate which comsolution calcium l-idonate.

2. Process of stabilizing an over-saturated solution of calcium gluconate which comprises adding to the calcium gluconate solution the calcium aldonate mixture lting from the hydrogenation of calcium 5-keto-gluconate.

3. Process of preparing a therapeutically useiui solution equivalent in calcium content to a 20% calcium gluconate solution, consisting in adding to a solution oi calcium gluconate in 12 times its weight of water, twice its weight of the mixed calcium aldonates resulting from the hydrogenation of calcium 5-keto-g'luconate.

4. Process of preparing a therapeutically useiul solution equivalent in calcium content to a 50% calcium gluconate solution consisting in adding the dried mixture resulting from the catalytic hydrogenation of calcium-5-keto-d-gluconate to an equal weight of water. i

RICHARD PASTERNACK. ELLIS V; BROWN. 

